Nucleoside antitumor agents have been widely used as effective chemotherapeutics for neoplastic cells. In their application as antitumor-chemotherapeutics, however, several problems have arisen. For example, in vivo enzymatic phosphorylation of the hydroxyl group at the 5'-position of the nucleoside anti-neoplastic agent is essential to activate its antitumor activity. In addition, the agent is decomposed to an inactive substance by enzymatic reactions such as phosphorolysis or deamination. Still further, the resistance of tumor cells to antitumor agents is known to progressively increase. Lastly, the agent is in sometimes toxic to normal mitotic cells. Many different nucleoside derivatives have been synthesized in an attempt to overcome the disadvantages of known nucleoside antitumor agents.
For example, a phospholipid conjugate, 5-fluoro-2'-deoxyuridine-5'-phosphate derivative (Japan Unexam. Patent Publ. No. 61-91195) has been reported.
Certain of the inventors have found that phospholipase D effectively catalyzes the transfer reaction of the phosphatidyl residue from glycerophospholipid to the primary hydroxyl group of a nucleoside, and hence a variety of nucleoside-phospholipid conjugates including arabinoside nucleoside-phospholipid conjugates can readily be prepared (U.S. Pat. No. 4,797,479).
The resistance of tumor cells to 5-fluorouracil (5-FU), a commonly used antitumor agent, is known. 2'-deoxy-5-trifluoromethyluridine is also known, which is effective against 5-FU-resistant cells and has antitumor and antiviral activities in vivo (Heiderberger et al., Cancer Res., Vol. 24, p. 1979 (1964), H. E. Kaufman et al., Science, Vol. 145, p. 585 (1964)). 2'-deoxy-5-trifluoromethyluridine is, however, decomposed by the action of thymidine phosphorylase in vivo, and is not effective for clinical use. Hence, 2'-deoxy-5-trifluorouridine derivatives which are effective against 5-FU-resistant tumor cells but which are not inactivated by nucleoside phosphorylase in vivo, are desired.